Mark Moran [00:00:03] Welcome to TGen Talks. I'm Mark Moran. Did you know that there are over 7,000 rare diseases and that they affect over 25 million Americans? Joining me today to discuss these often unknown and undiagnosed conditions is Dr. Vinodh Narayanan, co-founder and medical director of the Center for Rare Childhood Disorders, a group of scientists and clinicians working together to help patients with rare disorders. By the time many patients reach The Center they've experienced a diagnostic odyssey, countless trips to clinics and specialists in search of an answer. For many, the center offers their best hope. Dr. Narayanan, welcome.
Dr. Narayanan [00:00:47] Thank you very much, Mark.
Mark Moran [00:00:49] What makes the Center for Rare Childhood Disorders at TGen different? What's your approach when you see a new patient?
Dr. Narayanan [00:00:55] So I think our centers are unique, and that's the first one and only one in existence in Arizona. And we started in this, in our own odyssey, you know, as a part of TGen at a time when this technology was just being developed. And the technology I'm talking about is genomics. And, you know, TGen has translational genomics in its name and that's what we are all about. So the use of genomic technologies for diagnosis was something that we were pioneering here at TGen. And we've been in existence since 2012, applying state-of-the-art genomic technologies. And another very unique aspect of our center is that we have the clinical team and the bioinformatics team and the genomic scientists at TGen all working together at the same time. So we bring together the complete characterization of the patient, usually a child, you know, a comprehensive view of what that child looks like, what that child has been through, and bring that to bear when we are sitting down and analyzing hundreds and thousands of bits of data.
Mark Moran [00:02:14] We mentioned diagnostic odyssey by the time people get to The Center. They've been through one. What exactly is that? And what have some of the families tried before getting here?
Dr. Narayanan [00:02:25] Right. So it varies from child to child, but very often this diagnostic odyssey can take many years. I think a number I've heard quoted it is seven years. So these are families that are going from doctor to doctor, trying to find out what is wrong with their child. And, of course, conventional testing that might include things like an MRI scan of the brain, blood tests to look for metabolic alterations, invasive testing like a spinal tap, to look at spinal fluid or even biopsy of tissues like the muscle. So patients have gone through all of these tests, seen usually at least three or four specialists and still have no answer. And that's kind of the typical story of a family that reaches out to us.
Mark Moran [00:03:20] So very young child, five, six, seven years old, may have been poked, prodded, scanned, stuck with needles, been told things by doctors, and they still have no answer. Do you look at all at the overall mental and emotional health of the child who's going through something like that at such a young age?
Dr. Narayanan [00:03:40] Right. I think, you know, one has to address the issue of the whole family because it is, you know, the parents who are also going through the same ordeal as the children. The children are, of course, subjected to all of these diagnostic procedures that often don't result in an answer. But the parents go through the anguish. And I think the impact on a parent of not knowing what the problem is. I mean, it's just very difficult to underestimate that, you know, it is. Yes. In our cases where we are able to find an answer, the relief to that family that, OK, this is a diagnosable genetic condition. The value of that is just unmeasurable.
Mark Moran [00:04:30] What's the desperation like in their eyes and in their hearts when they show up here with their child?
Dr. Narayanan [00:04:34] I think they look upon TGen as the place of last resort. You know, they have gone through everything else and there's nowhere else they can turn. And sometimes, you know, diagnostic possibilities are not open to certain families because of money issues. You know, that their insurance plan, they're often covered by the state's AHCCCS Medicaid plans, and they do not cover any genetic testing at all, and we are their only resort. And, you know, for us, the issue of payment and money never enters into the picture. We're just in the research environment. So we have to explain what we do to them, obtain their consent, and then go forward.
Mark Moran [00:05:23] At TGen, as you like to say, that rare isn't so rare after all sometimes. What do you mean by that?
Dr. Narayanan [00:05:29] Well, I think as an aggregate, rare disorders make up a large number of conditions. So any one specific genetic abnormality may account for... It could be as rare as 100 or 200 children known around the entire world where their neurological problem is caused by a mutation in one specific gene. Sometimes it's more common than that it might be, you know, a few thousand patients, but when you pull all of them together, you know, multiplying a thousand patients by seven or eight thousand different genetic disorders, you see what the impact is. The numbers in the millions.
Mark Moran [00:06:12] When you were able to find a genetic component, for example, how are families impacted and how often are you able to give families answers?
Dr. Narayanan [00:06:22] Right. So I think so roughly of 50 percent of these families, we are able to come up with a precise genetic diagnosis. And when that happens and we you know, we are quite sure that A is the cause of B, then we sit down and meet with the families one on one. And I think this is the other side of TGen's Center that is very unique. There's a very personal way in which we counsel and return results to the families. We explain everything to them. You know, what does it mean to do your whole genome sequencing? What is it that we have found? Or how can we connect to this family, to the community of other families who might also have a child affected with a condition caused by this same gene mutation? So putting those families together and then putting the families in touch with the scientists around the world who may be researching that particular gene. So I think all of these things we do for the families. They are impacted to a great extent by that. You know, that there is hope that now that we know what is wrong, there is a way forward. The focus for them can be in connecting with other families, learning as much as they can, and learning what they can do for their child in light of the knowledge that they have gained.
Mark Moran [00:07:55] You touched on this earlier, but when you are able to look a parent in the eye and say, we have a definite answer, can you describe what their reaction is? What's the look in their eye? What's the emotion?
Dr. Narayanan [00:08:09] Yeah, I think that is hard to capture after going through, you know, 700 families. It does vary from family to family. I think some of them are elated to find an answer. And I think their reaction would be, OK, I don't have to go through any more testing. I don't have to put my child through any more invasive testing and we can focus on what to do for the child. So that is one and one reaction. Sometimes they just break down and cry. And, you know, the reason might vary from family to family always. You know, the question always comes up and we try to address this also, when we explain the results, one is that was it something that I did? You know, it's always buzzing in the back of their mind was especially the mothers, you know, who are bearing these children. Was it something that they did during the pregnancy or earlier on that could have caused this problem?
Mark Moran [00:09:15] You're listening to TGen Talks. I'm Mark Moran. We're visiting today with Dr. Vinodh Narayanan, co-founder and medical director of TGen's Center for Rare Childhood Disorders, a group of scientists and clinicians working together to help patients, often children with rare childhood disorders. Dr. Narayanan, besides the medical support, once you've made a diagnosis, where do you go from there?
Dr. Narayanan [00:09:38] Once we have arrived at a precise genetic diagnosis for a child. Of course, the first step is to counsel the family and part of that counseling involves searching the entire global published world literature so that we understand better what does that mean? What is the implication of that discovery? What is known about that gene? What is known about the protein? What is known about its function in the brain? And in the process of doing that, we are able to connect with scientists around the world, you know, especially the world's experts on any particular topic that might be willing to help us, but also might jump at the chance of working with biological specimens and tissues from our patients. So one of the things that we do here TGen it really happens once we find the genetic answer. If the families are willing, then we are able to do a small biopsy of the child's skin. It's a tiny little punch skin biopsy. It about a millimeter to two millimeters in size. And we bring that piece of skin to our lab and from that we grow cells from the patient. So this represents really the patient's own genetic material in a cellular form. And we can grow them up and share them with scientists around the world who might be able to use them to do their biological studies. And we can use them even as model systems in which we can test out treatments.
Mark Moran [00:11:30] So you're looking at ways to get past that amazing 50 percent rate you already have.
Dr. Narayanan [00:11:36] That's when the problem, our focus shifts. It's no longer what was the diagnosis, but now we can focus on what to do about it. And that means understanding the biology of the disease. How does that gene mutation affect brain development and what is already known? Are there drugs out there that have already been tried on a particular molecular pathway that we could repurpose for this child? And then, of course, connecting with the experts around the world.
Mark Moran [00:12:14] When you look back on this body of work that you have now, the great number of patients you have been able to help with the rare childhood disorders, how have some of your patients impacted you as not only a doctor but a human being?
Dr. Narayanan [00:12:28] Right. And I think that is a very difficult to measure. I think as a child neurologist, you know, I'm constantly learning. And I think the pace at which I've been forced to learn over these last eight years has been exponential compared to the previous 35 years of my career in neurology. I see every family as teaching me something. So I that's probably the biggest impact it has had on me as a neurologist. And I think they have made me a better neurologist.
Mark Moran [00:13:08] Do you have a couple of specific examples that stick out to you?
Dr. Narayanan [00:13:12] Examples of things where we have made a diagnosis? I think the one family that is very close to me and is a family right here in Phoenix, and I still remember this child coming to see me. This is probably 15 years, 16 years ago as an infant, you know, eight or nine-month-old infant probably having epileptic seizures at that time. And this was pre-genomic era where we didn't have these type of tools. And so we went through the usual conventional approach to figuring out what is wrong. MRIs, EEGs, blood tests, muscle biopsy, because I thought this child had a mitochondrial disorder, which is again a group of rare disorders. And it took about 11 years, and then, of course, we had by that time, we had created the center and we had enrolled a family in our center and that's when we found out what the real answer was. And it is a very rare disease. It's known now as DNN one encephalopathy. It has its own name and it's an epileptic condition. And we have dedicated a major effort in our research lab to understanding DNN one epileptic encephalopathy. We model it in little fish. We have a zebrafish colony here that we use to study the effect of this mutation.
Mark Moran [00:14:55] Who is your research shared with? Who do you collaborate with?
Dr. Narayanan [00:14:58] This particular project, the DNN one project is something that we have been doing by ourselves here TGen. My colleague Dr. Rangasamy, who is a Ph.D. scientist, is really the one that is in charge of all of that aspect of the work in our lab. My role is to provide guidance and make sure that the work we do has a direct impact on our patients understanding our patients' problem. We have recently joined up with another world-famous scientist in Texas who had a particular interest in this area. So we are it is a year in the in collaboration.
Mark Moran [00:15:45] What about in general? Who do you share information with or collaborate with from the Center for Rare Childhood Disorders?
Dr. Narayanan [00:15:51] There is a genomic data mining software that has been created by the scientists at Johns Hopkins. And it's called GeneMatcher. That's the name of the software. It allows people to connect with each other, people who are interested in a particular gene or in a particular mutation. So when we find something and we are not the experts in that particular area, the first thing we do is to enter that into our account in GeneMatcher. And it immediately is broadcast to scientists and clinicians around the world who also have to be members of the Gene Matcher family. And usually, within minutes, we make a connection with somebody.
Mark Moran [00:16:44] Wow. So this is a Match.com for people working in the genetic.
Dr. Narayanan [00:16:50] Exactly. Yes.
Mark Moran [00:16:52] Any exciting research coming out of The Center right now? Are you working at all with the CRISPR technology, for example?
Dr. Narayanan [00:16:59] CRISPR is an exciting, you know, development. That's why the discoverers of CRISPR have been given the Nobel Prize in medicine.
Mark Moran [00:17:08] So just for the record and why we refer to it as CRISPR. It stands for clustered regularly interspaced short palindromic repeats. I do think it's much easier to go with CRISPR, so I think we'll stick with it.
Dr. Narayanan [00:17:23] It has changed a lot about how we do research. For instance, in our research lab, one of our projects deals with a mitochondrial disease and it's looking at looking for a cure for two families right here in Arizona. And we have been able to create a mouse that models this exact mutation. And this we were able to do it in collaboration with Jackson Labs, which is a very big center for animal and mouse models, and that was done with the CRISPR technology. So it is kind of like a bacteria's immunological mechanism to protect the bacteria from viruses that are going to attack it. And what this CRISPR system does, it recognizes these invaders and produces a protein that destroys it. Basically, it's a search and destroy system.
Dr. Narayanan [00:18:27] Now, these scientists use that technology and modified it so that we can use this same technology, a RNA, a piece of RNA and a protein to go into the genetic material of a cell, target a particular location and change it to whatever we want. So that is what the technology is. And it's a way for doing what is called gene editing, some of the worrisome aspects of this technology. It could do things other than where you think it's going to do it.
Mark Moran [00:20:19] Of course, all scientific research takes money. What can a donor or potential donor expect?
Dr. Narayanan [00:20:27] I think all of the work we have done in these past eight years at the center would not have been possible were it not for the generous support of donors. Where there's donors donating, you know, 25 dollars or hundreds of thousands of dollars. Every little bit helps. Everything we do takes money, you know, the money to buy the reagents, to do the sequencing money to support the people who are doing the work, the analysis of the genomes and of course, the research work. I think this donation and support in that way is critical to get us to a point of maturity so that we can apply for government, you know, a national foundation, NIH funding for specific research projects.
Dr. Narayanan [00:21:23] How would they get in touch with you to talk about becoming involved?
Mark Moran [00:21:27] I think the best way for people who are thinking, even contemplating, supporting the Center for Childhood Disorders is to reach out to the TGen Foundation. I think they have been incredibly supportive and all donations to TGen are channeled through the foundation and they could earmark donations for any particular purpose, whether it's cancer or non-cancer, for the center. You know, they just have to designate that as the recipient of their generous donation.
Mark Moran [00:21:58] The TGen Center for Rare Childhood Disorders, where rare isn't so rare, happening right here in Phoenix, Arizona. Dr. Narayanan, thank you so much for your time, your important work and your insights today. We appreciate you being here.
Dr. Narayanan [00:22:13] Thank you very much for having me here.
Mark Moran [00:22:15] Dr. Vinodh Narayanan is the medical director of TGen Center for Rare Childhood Disorders. To learn more, visit our Web site at TGen.org/Center. You can listen to more TGen Talks at TGen.org/TGenTalks. TGen is an affiliate of City of Hope. Thanks for listening to TGen Talks. I'm Mark Moran.